ALS as a systemic disease
Understanding the extra-motor manifestations of ALS
Many people living with motor neuron disease will experience cognitive dysfunction during their disease. In fact, motor neuron disease is now considered part of the same disease spectrum of frontotemporal dementia, characterised by cognitive dysfunction in behaviour, language, fluency and executive functioning. Our group have created several deeply-phenotyped post-mortem tissue cohorts to try to understand what makes some people more susceptible to these non-motor/cognitive symptoms, something that we hope will allow us to open therapeutic avenues for susceptible individuals in the future. Our group are also interested in non-central nervous system manifestations of motor neuron disease. Non-neurological symptoms are common in people with motor neuron disease, and we showed recently that the same pathology that is seen in the brain at post-mortem can be seen in non-central nervous system tissues (particularly gut tissues) many years prior to motor or cognitive symptom onset. This could provide us with a biomarker for early diagnosis and possibly even improve chances for early therapeutic intervention.
Pathomechanisms of protein misfolding
Inflammation & molecular crowding in ALS
One of the unifying pathological features in the majority of neurodegenerative diseases is the presence of aberrantly misfolded intra- and extra-cellular protein aggregates. These aggregates are present in the central nervous system at post-mortem, but our group was the first to show that these aggregates are also present in non-CNS tissues many years prior to neurological symptom onset in motor neuron disease. We are interested in common pathomechanisms that could be driving this aggregation in different CNS and non-CNS organs. Our central hypothesis for this work is that aggregation and cellular dysfunction is precipitated by crowding of the intracellular environment potentiating the aggregation of aggregation-prone proteins and preventing their disassembly. We believe that this could be potentiated by extrinsic pressure on cells, caused by inflammation and extracellular oedema, constricting their environment resulting in compression that reduces cell volume. Indeed, we see distinct inflammatory activation signatures in sequencing data from motor neuron disease patients. Our group is interested in investigating specific mechanisms of inflammation and understanding how these mechanisms could be manipulated therapeutically.
Clinical & Pre-clinical Data Science
As a clinician scientist, I am keen to facilitate the translation of experimental science to the clinic. As part of this research theme, our group regularly perform systematic-reviews and meta-analyses, spanning a wide range of clinical questions, including evaluations of both the preclinical and clinical literature. Data quality assessments and research recommendations are also an integral part of our approach. Examples of previous projects are listed below. This research is particularly useful for undergraduates (clinical and non-clinical), PhD students and early career researchers who want to gain a better understanding of a particular research topic and often results in high-value translational publications. We often have projects ongoing in this area and are happy to design new bespoke projects for individuals to lead on, so get in touch if you are interested.
Here is a list of some of our collaborators, past and present:
Dr. Neil Shneider (Columbia University/Elanour & Lou Gerrig ALS Centre)
Dr. Chris Sibley (University of Edinburgh)
Dr. Mathew Horrocks (University of Edinburgh)
Dr. Hemali Phatnani (New York Genome Centre)
Prof. Sharon Abrahams (University of Edinburgh)
Prof. Gian Gaetano Tartaglia (Italian Institute of Technology; Centre for Human Technologies, Genoa)
Prof. Mark Wilson (University of Wollongong)
Dr. James Longden (e-therapeutics PLC, Edinburgh)
Dr. Valeria Gerbino (Fondazione Santa Lucia, Rome)
Prof. Tom Maniatis (Columbia University)
Prof. Ai Yamamoto (Columbia University)
Prof. Liam Holt (New York University)
Prof. Simon Parson (University of Aberdeen)
Prof. Thomas Bak (University of Edinburgh)